Use of low dose amount of aldosterone antagonist for treatment of cardiovascular disease

ABSTRACT

Use of low dosages of an aldosterone receptor antagonist, such as spironolactone, is described for use in treatment of circulatory disorders. This therapy would be particularly useful to treat congestive heart failure while avoiding or reducing aldosterone-antagonist-induced side effects, such as hyperkalemia.

FIELD OF THE INVENTION

[0001] Use of an aldosterone receptor antagonist is described for use intreatment of circulatory disorders, including cardiovascular diseasessuch as heart failure, hypertension and congestive heart failure. Ofparticular interest is a therapy using spirolactone-type aldosteronereceptor antagonist compound at a low dosage at which side-effects ofthe aldosterone receptor antagonist are reduced or avoided.

BACKGROUND OF THE INVENTION

[0002] Myocardial (or cardiac) failure, whether a consequence orprevious myocardial infarction(s), heart disease associated withhypertension, or primary cardiomyopathy, is a major health problem ofworldwide proportions. The incidence of symptomatic heart failure hasrisen steadily over the past several decades.

[0003] In clinical terms, decompensated cardiac failure consists of aconstellation of signs and symptoms that arise from congested organs andhypoperfused tissues to form the congestive heart failure (CHF)syndrome. Congestion is caused largely by increased venous pressure andby inadequate sodium (Na⁺) excretion, relative to dietary Na⁺ intake,and is importantly related to circulating levels of aldosterone (ALDO).An abnormal retention of Na⁺ occurs via tubular epithelial cellsthroughout the nephron, including the later portion of the distal tubuleand cortical collecting ducts, where ALDO receptor sites are present.

[0004] ALDO is the body's most potent mineralocorticoid hormone. Asconnoted by the term mineralocorticoid, this steroid hormone hasmineral-regulating activity. It promotes Na+ reabsorption not only inthe kidney, but also from the lower gastrointestinal tract and salivaryand sweat glands, each of which represents classic ALDO-responsivetissues. ALDO regulates Na+ and water resorption at the expense ofpotassium (K⁺) and magnesium (Mg²⁺) excretion.

[0005] ALDO can also provoke responses in nonepithelial cells. Elicitedby a chronic elevation in plasma ALDO level that is inappropriaterelative to dietary Na⁺ intake, these responses can have adverseconsequences on the structure of the cardiovascular system. Hence, ALDOcan contribute to the progressive nature of myocardial failure formultiple reasons.

[0006] Multiple factors regulate ALDO synthesis and metabolism, many ofwhich are operative in the patient with myocardial failure. Theseinclude renin as well as non-renin-dependent factors (such as K⁺, ACTH)that promote ALDO synthesis. Hepatic blood flow, by regulating theclearance of circulating ALDO, helps determine its plasma concentration,an important factor in heart failure characterized by reduction incardiac output and hepatic blood flow.

[0007] The renin-angiotensin-aldosterone system (“RAAS”) is one of thehormonal mechanisms involved in regulating pressure/volume homeostasisand also in the development of hypertension, a precursor conditonimplicated in the progression of more serious cardiovascular diseasessuch as congestive heart failure. Activation of therenin-angiotensin-aldosterone system begins with secretion of the enzymerenin from the juxtaglomerular cells in the kidney. The enzyme reninacts on a naturally-occurring substrate, angiotensinogen, to release adecapeptide, Angiotensin I. This decapeptide is cleaved by angiotensinconverting enzyme (“ACE”) to provide an octapeptide, Angiotensin II, theprimary active species of this system. This octapeptide, angiotensin II,is a potent vasoconstrictor and also produces other physiologicaleffects such as stimulating aldosterone secretion, promoting sodium andfluid retention, inhibiting renin secretion, increasing sympatheticnervous system activity, stimulating vasopressin secretion, causingpositive cardiac inotropic effect and modulating other hormonal systems.

[0008] Emphasis has been placed on minimizing hyperaldosteronism as abasis for optimizing patient treatment. This includes the importance ofALDO-receptor antagonism both in patients treated with conventionaldiuretic programs and in patients treated with angiotensin-convertingenzyme (ACE) inhibitors, who are often constrained to small doses of ACEinhibitor because of orthostatic hypotension. Such patients maydemonstrate a recurrence of heart failure symptoms likely related toelevations in plasma ALDO levels.

[0009] Many aldosterone receptor blocking drugs and their effects inhumans are known. For example, spironolactone is a drug which acts atthe mineralocorticoid receptor level by competitively inhibitingaldosterone binding. This steroidal compound has been used for blockingaldosterone-dependent sodium transport in the distal tubule of thekidney in order to reduce edema and to treat essential hypertension andprimary hyperaldosteronism [F. Mantero et al, Clin. Sci. Mol. Med., 45(Suppl 1), 219s-224s (1973)]. Spironolactone is also used commonly inthe treatment of other hyperaldosterone-related diseases such as livercirrhosis and congestive heart failure [F. J. Saunders et al, Aldactone;Spironolactone: A Comprehensive Review, Searle, N.Y. (1978)].Progressively-increasing doses of spironolactone from 1 mg to 400 mg perday [i.e., 1 mg/day, 5 mg/day, 20 mg/day] was administered to aspironolaccone-intolerant patient to treat cirrhosis-related ascites [P.A. Greenberger et al, N. Eng. Reg. Allergy Proc., 7(4), 343-345(July-August, 1986)]. It has been recognized that development ofmyocardial fibrosis is sensitive to circulating levels of bothAngiotensin II and aldosterone, and that the aldosterone antagonistspironolactone prevents myocardial fibrosis in animal models, therebylinking aldosterone to excessive collagen deposition [D. Klug et al, Am.J. Cardiol., 71 (3), 46A-54A (1993)]. Spironolactone has been shown toprevent fibrosis in animal models irrespective of the development ofleft ventricular hypertrophy and the presence of hypertension [C. G.Brilla et al, J. Mol. Cell. Cardiol., 25 (5), 563-575 (1993)].Spironolactone at a dosage ranging from 25 mg to 100 mg daily is used totreat diuretic-induced hypokalemia, when orally-administered potassiumsupplements or other potassium-sparing regimens are consideredinappropriate [Physicians' Desk Reference, 46th Edn., p. 2153, MedicalEconomics Company Inc., Montvale, N.J. (1992)].

[0010] Previous studies have shown that inhibiting ACE inhibits therenin-angiotensin system by substantially complete blockade of theformation of angiotensin II. Many ACE inhibitors have been usedclinically to control hypertension. While ACE inhibitors may effectivelycontrol hypertension, side effects are common including chronic cough,skin rash, Loss of taste sense, proteinuria and neutropenia.

[0011] Moreover, although ACE inhibitors effectively block the formationof Angiotensin II, aldosterone levels are not well controlled in certainpatients having cardiovascular diseases. For example, despite continuedACE inhibition in hypertensive patients receiving captopril, there hasbeen observed a gradual return of plasma aldosterone to baseline levels[J. Staessen et al, J. Endocrinol., 91, 457-465 (1981)]. A similareffect has been observed for patients with myocardial infarctionreceiving zofenopril [C. Borghi et al, J. Clin. Pharmacol., 33, 40-45(1993)]. This phenomenon has been termed “aldosterone escape”.

[0012] In a side-by-side treatment of two cohorts of rats, one cohorttreated with spironolactone sub-cutaneously and the other cohort treatedwith captopril, spironolactone was found to prevent fibrosis in thehypertensive-rat cohort [C. G. Brilla et al, J. Mol. Cell. Cardiol., 25,563-75 (1993)].

SUMMARY OF DRAWING FIGURES

[0013]FIG. 1 shows urinary aldosterone levels at different rates ofspironolactone administration (12.5 mg/25 mg/50 mg/75 mg), as comparedto placebo.

[0014]FIG. 2 shows plasma renin activity at different rates ofspironolactone administration (12.5 mg/25 mg/50 mg/75 mg), as comparedto placebo.

[0015]FIG. 3 shows N-Terminal ANF levels at different rates ofspironolactone administration (12.5 mg/25 mg/50 mg/75 mg), as comparedto placebo.

[0016]FIG. 4 shows changes in supine blood pressure at different ratesof spironolactone administration (12.5 mg/25 mg/50 mg/75 mg), ascompared to placebo.

[0017]FIG. 5 shows changes in supine heart rate at different rates ofspironolactone administration(12.5 mg/25 mg/50 mg/75 mg), as compared toplacebo.

SUMMARY OF THE INVENTION

[0018] Treatment of circulatory disorders, including cardiovasculardisorders such as heart failure, hypertension and congestive heartfailure is provided by a therapy comprising use of atherapeutically-effective amount of a spirolactone-type aldosteronereceptor antagonist. Preferably, the spirolactone-type aldosteronereceptor antagonist is administered in the therapy at a low dose, thatis at a dose lower than has been conventionally used in clinicalsituations.

[0019] The phrase “aldosterone receptor antagonist” embraces an agent orcompound, or a combination of two or more of such agents or compounds,which agent or compound binds to the aldosterone receptor as acompetitive inhibitor of the action of aldosterone itself at thereceptor site in the renal tubules, so as to modulate thereceptor-mediated activity of aldosterone. Typical of such aldosteronereceptor antagonists are spirolactone-type compounds. The term“spirolactone-type” is intended to characterize a steroidal structurecomprising a lactone moiety attached to a steroid nucleus, typically atthe steroid “D” ring, through a spiro bond configuration.

[0020] The phrase “therapeutically-effective” is intended to qualify theamount of aldosterone receptor antagonist agent for use in the therapywhich will achieve the goal of improvement in cardiac sufficiency byreducing or preventing, for example, the progression of congestive heartfailure, while avoiding adverse side effects typically associated withsuch agent.

[0021] The phrase “low-dose amount”, in characterizing atherapeutically-effective amount of the aldosterone receptor antagonistagent in the combination therapy, is intended to define a quantity ofsuch agent, or a range of quantity of such agent, that is capable ofimproving cardiac sufficiency while reducing or avoiding one or morealdosterone-antagonist-induced side effects, such as hyperkalemia. Adosage of spironolactone which would accomplish the therapic goal offavorably enhancing cardiac sufficiency, while inducing or avoiding sideeffects, would be a dosage that substantially avoids inducing diuresis,that is, a substantially non-diuresis-effect dosage.

[0022] A family of spirolactone-type compounds of interest is defined byFormula I

[0023] wherein R is lower alkyl of up to 5 carbon atoms, and

[0024] Lower alkyl residues include branched and un-branched groups,preferably methyl, ethyl and n-propyl.

[0025] Specific compounds of interest within Formula I are thefollowing:

[0026]7α-Aceylythio-3-oxo-4,15-androstadiene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one;

[0027]3-Oxo-7α-propionylthio-4,15-androstadiene-[17((β-1′)-spiro-5′]perhydrofuran-2′-one;

[0028]6β,7β-Methylene-3-oxo4,15-androstadiene-[17((β-1′)-spiro-5′]perhydrofuran-2′-one;

[0029]15α,16α-Methylene-3-oxo-4,7α-propionylthio-4-androstene[17(β-1′)-spiro-5′]perhydrofuran-2′-one;

[0030]6β,7β,15α,16α-Dimethylene-3-oxo-4-androstene[17(β-1′)-spiro-5′]perhydrofuran-2′-one;

[0031]7α-Aceylythio-15β,16β-Methylene-3-oxo-4-androstene-[17(β-1′)-spiro-5]perhydrofuran-2′-one;

[0032]15β,16β-Methylene-3-oxo-7β-propionylthio-4-androstene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one;and

[0033]6β,7β,15β,16β-Dimethylene-3-oxo-4-androstene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one.

[0034] Methods to make compounds of Formula I are described in U.S. Pat.No. 4,129,564 to Wiechart et al issued on 12 Dec. 1978.

[0035] A second family of spirolactone-type compounds of interest isdefined by Formula II:

[0036] wherein

[0037] R¹ is C₁₋₃-alkyl or C₁₋₃ acyl and R² is hydrogen or C₁₋₃-alkyl.

[0038] Specific compounds of interest within Formula II are thefollowing:

[0039]1α-Acetylthio-15β,16β-methylene-7α-methylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone;and

[0040]15β,16β-Methylene-1α,7α-dimethylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone.

[0041] Methods to make the compounds of Formula II are decribed in U.S.Pat. No. 4,789,668 to Nickisch et al which issued 6 Dec. 1988.

[0042] A third family of spirolactone-type compounds of interest isdefined by a structure of Formula III:

[0043] Specific compounds of interest include:

[0044] 7α-Acylthio-21-hydroxy-3-oxo-17α-pregn-4-ene-17-carboxylic acidlactones; and

[0045] 21-hydroxy-3-oxo-17α-pregn-1,4-diene-17-carboxylic acid lactone.

[0046] Methods to make the compounds of Formula II are described in U.S.Pat. No. 3,257,390 to Patchett which issued 21 Jun. 1966. Of particularinterest is the compound spironolactone having the following structureand formal name:

[0047] “spironolactone”:17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate

[0048] Spironolactone is sold by G.D. Searle & Co., Skokie, Ill., underthe trademark “ALDACTONE”, in tablet dosage form at doses of 25 mg, 50mg and 100 mg per tablet.

[0049] A diuretic agent may be used in combination with aldosteronereceptor antagonist. Such diuretic agent may be selected from severalknown classes, such as thiazides and related sulfonamides,potassium-sparing diuretics, loop diuretics and organic mercurialdiuretics.

[0050] Examples of thiazides are bendroflumethiazide, benzthiazide,chlorothiazide, cyclothiazide, hydrochlorothiazide, hydroflumethiazide,methyclothiazide, polythiazide and trichlormethiazide.

[0051] Examples of sulfonamides related to thiazides are chlorthalidone,quinethazone and metolazone.

[0052] Examples of potassium-sparing diuretics are triameterene andamiloride.

[0053] Examples of loop diuretics, i.e., diuretics acting in theascending limb of the loop of Henle of the kidney, are furosemide andethynacrylic acid.

[0054] Examples of organic mercurial diuretics are mercaptomerin sodium,merethoxylline procaine and mersalyl with theophylline.

Biological Evaluation

[0055] A combination therapy of ACE inhibitor and spironolactone wasevaluated in humans as described in the following clinical trials.

Methods

[0056] Patients

[0057] Two-hundred fourteen (214) patients with symptomatic heartfailure had an ejection fraction ≦35%, a history of New York HeartAssociation (NYHA) functional classification III-IV six months prior toenrollment, and current classification II-IV were randomized among fivetreatment groups. Patients were assigned to receive eitherspironolactone 12.5 mg (41 patients), 25 mg (45 patients), 50 mg (47patients), 75 mg (41 patients), or placebo (40 patients) once a day for12 weeks. Two patients that were randomized failed to take the studymedication and were excluded from the analysis.

[0058] All patients were taking a stable dose of ACE inhibitor, loopdiuretic, and optional digitalis for 30 days prior to the first dose ofstudy medication. Potassium supplement therapy that was stable for 14days prior to the first dose of study medication was also allowed.

[0059] Informed consent was obtained from all patients, and the protocolwas approved by each ethical committee. At enrollment all patients hadnormal serum potassium values (<5.5 mmol/L) and creatinine values of≦2.0 mg/dL or ≦180 mmol/L. Patients were excluded from enrollment ifthey: (1) were diagnosed with either an acute life-threatening disease(included patients with automatic implantablecardioverter/defibrillator), valvular disease, unstable angina,insulin-dependent diabetes, cancer (without a reoccurrence within thelast five years), or primary hepatic failure; (2) were on a waiting listfor a heart transplant or experienced a myocardial infarction 30 daysprior to the first dose of study medication; (3) had laboratory valuesfor hematology or biochemistry considered abnormal and clinicallysignificant prior to the first dose of study medication; (4) received apotassium spacing diuretic within 30 days prior to the first dose ofstudy medication.; (5) were receiving, on a regular basis, eithernon-steroidal anti-inflammatory drugs or aspirin >325 mg/day, steroids,dopamine agonists or antagonists, insulin or heparin; (6) were on anyinvestigational medication within 30 days of the first dose ofmedication.

[0060] Study Design

[0061] This was a multinational, double-blind, randomized, parallelgroup study.

[0062] Laboratory Measurements

[0063] The following information was obtained from each patient atbaseline:

[0064] 1. Concurrent medication within the past 30 days.

[0065] 2. 12-lead ECG

[0066] 3. Cardiac assessments that included blood pressure, pulse,sodium retention score (general assessment of a patient's edematousstate was derived from the summation of scores obtained from Table I),NYHA classification, and

[0067] 4. Signs and symptoms within the past 30 days. TABLE I SodiumRetention Score Parameters Grade Assessment Rales 0 Absent of lungs 1 Inlower ⅓ of lungs 2 In lower ⅔ of lungs 3 In all lung fields Peripheral 0Absent Pitting Edema 1 Trace 2 Limited to ankles 3 Not limited to ankles4 Anasarca Weight Change −1 Decreased 0 Unchanged 1 IncreasedHepatomegaly 0 Absent 1 Present S3 Gallop 0 Absent 1 Present Increased 0Absent Jugular 1 Present Venous Pressure

[0068] The following laboratory values were obtained at the pretreatmentvisit:

[0069] Hematology: White blood cell count (WBC), hematocrit, hemoglobin,platelet count.

[0070] Biochemistry: Creatinine, potassium, AST, SGOT, urinarysodium/potassium ratio, bicarbonate, calcium, chloride, creatinine,creatinine clearence, magnesium, glucose, urea, uric acid.

[0071] Neurohormones: Plasma renin activity, pro-atrial natriureticfactor, urinary aldosterone.

[0072] Blood and urine samples were centrally analyzed at SciCorLaboratories. Laboratory values for urinary aldosterone and renin levelswere done at the Ohio State University Laboratory in Columbus, Ohio.Pro-atrial natriuretic factor samples were evaluated at the Universityof Oslo Laboratory in Oslo, Norway.

[0073] Patients were evaluated 9 days after beginning study medication.Documented changes in concurrent medications, signs and symptoms anddrug compliance were recorded. These procedures were repeated at Week 4and Week 8 visits. Patient information and procedures on the final visit(Week 12) was identical to the pre-treatment visit.

Statistical Analysis General Methods

[0074] Analysis of cardiac assessment changes in patient therapy andvital signs were performed for both the Intent-to-Treat (ITT) andevaluable patient groups. Analysis of demographic variables, adverseevents and clinical laboratory values were performed in the ITT group.

[0075] For each efficacy variable, results of each visit were examinedseparately. An appropriate trend test was used to test for overalldose-response. Pair-wise comparisons were made for each active dose toplacebo. Significant levels for pair-wise comparisons were adjustedusing the Hochberg-Bonferromi method to maintain the overall Type Ierror rate. All statistical methods were two-sided.

Results

[0076] Recruitment

[0077] Two-hundred and fourteen patients were recruited from 22 studysites in eleven countries.

[0078] Patient Characteristics

[0079] Patient demographic, vital signs, and cardiac status at baselineare summarized in Table II. TABLE II Patient Demographics SpironolactoneSpironolactone Spironolactone Spironolactone p- Demographic 12.5 mg/d 25mg/d 50 mg/d 75 mg/d Plac bo Value Age (years) 63 ± 12 61 ± 9 62 ± 13 62± 13 61 ± 12 N.S. Caucasian/other (%) 93/7  98/2  93/7  88/12 97/3  N.S.Male/female (%) 78/22 82/18 74/26 88/12 83/18 N.S. Vital Signs Weight(kg) 74 75 73 78 73 N.S. Blood pressure (mmHg) Systolic 121 120 121 125121 N.S. Diastolic 76 76 75 81 74 N.S. Pulse (bpm) 76 74 76 74 71 N.S.Cardiac Status NYHA (%) II 63 60 43 49 38 III 34 38 55 49 60 IV 2 2 2 22 N.S. Sodium retention score Mean value 1.54 1.62 1.64 1.61 1.78 N.S.ACE-I (Mean dose) Captopril (mg) 57.3 57.5 69.7 59.4 65.4 N.S. Enalapril(mg) 16.4 13.4 14.5 16.3 10.8 N.S. Loop Diuretic (Mean dose) Furosemide(mg) 58.8 82.8 76.9 84.9 63.2 N.S. Digoxin (%) 78.0 77.8 76.6 80.5 77.5N.S. Potassium supplement 43.9 37.8 34.0 39.0 30.0 N.S. (%)

[0080] Patients ranged in age from 26 to 83 years (mean=60), 81% weremale, 94% were Caucasian. At baseline 51% of the patients were NYHAClass II, 47% were Class III. With respect to sodium retention score, astatistically significant dose response was seen at Day 9 with higherdoses showing more reduction in sodium retention score (p=0.019).However, this effect was not seen at later visits (p>0.20). There was animprovement in NYHA Class placebo group and in all the spironolactonegroups. Although a trend toward improvement in the spironolactone groupwas observed, the difference was not statistically significant.

[0081] Chances in Patient Therapy

[0082] The treatment groups did not differ significantly with respect tochanges in dose of ACE inhibitor, digitalis or potassium supplements atany visit (p≦0.11). The treatment groups did differ significantly withrespect to changes in loop diuretic therapy only at Week 8 (p=0.004) inthat more patients on the higher doses of spironolactone had decreasesin the loop diuretic dose compared to the placebo group. This patternwas not observed at Week 12.

[0083] Chances in Vital Signs

[0084] Changes from baseline in vital signs at Week 12 are summarized inTable III. TABLE III Mean Change in Weight and Vital Signs from Baselineto Week 12 Spironolactone Spironolactone Spironolactone Spironolactonep- 12.5 mg/d 25 mg/d 50 mg/d 75 mg/d Placebo Value Weight 0.59 (3.00)−0.16 (3.02) 0.62 (2.05) −0.81 (2.70) 0.11 (2.46) 0.109 Supine systolicBP 1.84 (11.82) −4.46 (13.97) −7.04 (15.83) −5.68 (15.62) 0.22 (13.45)0.036 Supine diastolic BP −0.19 (9.13) −2.74 (9.57) −5.11 (11.11) −5.91(9.05) 1.78 (7.84) 0.014 Supine pulse (BPM) −3.70 (9.56) −1.40 (10.00)−3.21 (11.27) −1.07 (13.79) 1.42 (9.69) 0.422

[0085] At all visits the 25 mg, 50 mg, and 75 mg groups had decreases inmean systolic and diastolic blood pressure, while the placebo group hadincreases in mean systolic and diastolic blood pressure (both standingand supine). Dose response with respect to standing and supine diastolicblood pressure was statistically significant for all visits (p≦0.002).Dose response with respect to standing and supine blood pressure wasstatistically significant at Week 4, Week 8, and Week 12 (p≦0.033), butnot at Day 9 (p≧0.12).

[0086] No significant between-treatment differences in change frombaseline in pulse were observed at any visit (p-values≧0.136). Astatistically significant dose response with greater decreases in pulsein the supine position at higher doses was observed at Week 4(p-value=0.045). Spironolactone doses of 25 and 50 mg were alsosignificantly different from placebo (p-values≦0.043) (See Graph 1).

[0087] At Day 9 and Week 4 visits, there was a statistically significantdose response with respect to changes from baseline in body weight inthat patients in the 75 mg dose group experienced more weight loss thanother patients. This dose response was not observed at later visits(p≧0.062).

[0088] Clinical Laboratory Values

[0089] Table IV contains details of the different clinical laboratoryvalues that showed statistically significant treatment differences withrespect to mean changes at Week 12 visit compared with their respectivebaseline value. TABLE IV Weak 12 Mean Change SpironolactoneSpironolactone Spironolactone Spironolactone p- 12.5 mg/d 25 mg/d 50mg/d 75 mg/d Placebo Value Urinary aldosterone (nmol/D) 4.21 4.27 8.1111.13 0.76 0.002 N-Terminal ANF (pmol/L) −287.30 −294.60 −351.30 −370.6054.50 0.022 PRA (NgAngl/L/s) 9.90 9.33 13.18 10.23 0.50 0.002 Hematocrit(%) 0.00 −0.02 −0.02 −0.03 0.00 0.002 Hemoglobin (mmol/L/Fe) 0.12 −0.20−0.31 −0.46 0.00 0.005 Potassium (mmol/L) 0.18 0.37 0.51 0.58 −0.100.001 Creatinine (umol/L) 6.83 9.30 14.06 21.90 −1.96 0.001 Sodium(mmol/L) −1.61 −1.85 −2.52 −3.37 −0.03 0.001

[0090] Urinary Aldosterone (See Graph 2)

[0091] Urinary aldosterone was determined only for baseline and the 12week visit. Urinary aldosterone excretion showed mean increases frombaseline in all treatment groups (P≦0.012). Greater increases were seenat higher doses of spironolactone (p=0.002). All pair-wise comparisonsbetween active treatment and placebo were statistically significant(p≦0.009).

[0092] N-Terminal Atrial Natriuretic Factor (ANF) (See Graph 2)

[0093] All active treatments showed decreases from baseline at alltreatment visits. Dose-response was statistically significant at Day 9(p=0.048), Week 4 (p=0.005), and Week 12 (p=0.008). ANF was not measuredat Week 8. In comparisons the 50 mg dose group differed significantlyfrom placebo at Week 4 (p=0.009) and Week 12 (p=0.006), while the 75 mgdose group differed significantly from placebo at Week 12 only(p=0.007).

[0094] Plasma Renin Activity (PRA) (See Graph 2)

[0095] A statistically significant dose-response with respect to changefrom baseline in PRA was seen at Day 9, Week 4 and Week 12 (P≦0.001)with higher doses of spironolactone associated with greater increases inPRA. PRA was not measured at Week 8.

[0096] Hematocrit and Hemoglobin

[0097] At Day 9 visit a statistically significant mean value differencebetween placebo and the different active treatments was observed withlower values for the placebo group than the active treatments (p<0.001).At Week 12 a reverse statistically significant difference was observedwith lower levels for the active treatment groups for hematocrit(p=0.002) and hemoglobin (0.005).

[0098] Serum Potassium

[0099] A statistically significant dose-response with respect to changefrom baseline in serum potassium was seen at all treatment period visits(p<0.001). Higher doses of spironolactone were associated with largerincreases in potassium. All doses of active treatment had significantlyhigher serum potassium levels relative to baseline than placebo(p≦0.034).

[0100] Incidence of Hyperkalemia Treatment: SpironolactoneSpironolactone Spironolactone Spironolactone Placebo 12.5 mg/d 25 mg/d50 mg/d 75 mg/d Patients (%) 2 (5%) 2 (5%) 6 (13%) 9 (20%) 10 (24%)

[0101] Predictors of Hyperkalemia

[0102] Seven possible predictors of hyperkalemia (potassium ≧25.5mmol/L) were included in a step-wise Cox regression analysis: randomizedtreatment (treated as a categorical variable), age, baseline NYHA class,baseline serum potassium, baseline PRA, baseline creatinine, baselineurinary aldosterone, and type and dose of ACE-I. Besides the dose ofspironolactone, the following predictors of hyperkalemia werestatistically significant in the step-wise regression analysis: type ofACE-I (captopril versus other), baseline serum creatinine, and baselineserum potassium. Results are summarized as follows: Factor p-value RiskRatio Captopril vs other ACE-I 0.013 0.318 Serum Creatinine > normal0.038 2.72 Baseline Potassium > median 0.040 2.32

[0103] In this analysis, the risk ratio can be thought of as theprobability that the patient with the risk factor will develophyperkalemia, relative to the probability that a patient without therisk factor will develop it. (For example, patients on captopril areabout one-third as likely to develop hyperkalemia as a patient onanother ACE-I.) Risk ratios relative to placebo for she various doses ofspironolaccone are: Dose p-value Risk Ratio Spironolactone 12.5 mg 0.981.02 Spironolactone 25 mg 0.19 2.91 Spironolactone 50 mg 0.034 5.32Spironolactone 75 mg 0.016 6.66

[0104] After adjusting for the above factors, other predictors includedin the step-wise regression analysis were not significant(p-values≧0.07). However, the following additional factor wassignificantly related to the development of hyperkalemia when consideredapart from other predictors except the dose of spironolactone. Factorp-value Risk Ratio High ACE-I Dose 0.050 2.93

[0105] Serum Magnesium

[0106] Change from baseline in serum magnesium showed a statisticallysignificant dose-response at Day 9 and Week 4 (p≦0.048), with morepatients in the placebo group showing decreases in serum magnesium.However, this effect was not seen at later visits (p≧0.083).

[0107] Adverse Effects

[0108] Table V summarizes the twelve most common adverse events bydifferent treatment groups. Only one symptom, hyperkalemia, showed aclear dose-response in term of incidence (p=0.001). TABLE V Incidence ofAdverse Events Spironolactone Dose-Ranging Study Intent-to-Treat Cohort(Top Twelve Events) Treatment Group (Percentage of Patients)Spironolactone Spironolactone Spironolactone Spironolactone AdverseEvents 12.5 mg 25 mg 50 mg 75 mg Placebo Total Dyspnea 22.0 15.6 26.124.4 30.0 23.5 Angina Pectoris 19.5 20.0 8.7 14.6 17.5 16.0 Dizziness12.2 13.3 13.0 17.1 15.0 14.1 Fatigue 12.2 13.3 15.2 14.6 15.0 14.1Nausea 2.4 17.8 6.5 19.5 12.5 11.7 Diarrhea 4.9 22.2 8.7 14.6 5.0 11.3Abdominal Pain 7.3 8.9 13.0 7.3 17.5 10.8 Headache 9.8 2.2 15.2 7.3 20.010.8 Hyperkalemia 2.4 8.9 15.2 19.5 2.5 9.9 URT Infection 4.9 11.1 8.72.4 12.5 8.0 Arthralgia 4.9 4.4 8.7 4.9 7.5 6.1 Coughing 4.9 2.2 4.3 2.412.5 5.2

[0109] A breakdown of the hospitalizations is as follows: TreatmentPlacebo 12.5 mg 25 mg 50 mg 75 mg P Patients (%) 5 (12.5%) 3 (7.3%) 3(6.6%) 13 (27.6%) 6 (14.6%) N.S.

[0110] No deaths were reported during the drug treatment period. Threepatients died within 30 days after the study was completed. These threepatients were previously at the 50 mg dose.

[0111] Administration of the aldosterone receptor antagonist may beaccomplished by oral route, or by intravenous, intramuscular orsubcutaneous injections. If a diuretic is used in co-therapy, with thealdosterone receptor antagonist, then administration may take placesequentially in separate formulations, or may be accomplished bysimultaneous administration in a single formulation or separateformulations. The formulation may be in the form of a bolus, or in theform of aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solution and suspensions may be prepared from sterilepowders or granules having one or more pharmaceutically-acceptablecarriers or diluents, or a binder such as gelatin orhydroxypropyl-methyl cellulose, together with one or more of alubricant, preservative, surface-active or dispersing agent.

[0112] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. A suitable daily dose fora mammal may vary widely depending on the condition of the patient andother factors. The ALDO antagonist may be present in an amount of fromabout 1 to 400 mg, preferably from about 2 to 150 mg, depending upon thespecific ALDO antagonist compound selected and the specific diseasestate being tangetted for the combination therapy. If a diuretic agentis used in co-therapy, then such agent may be present in an amount fromabout 1 mg to about 400 mg per dose, and more preferably from about 1 mgto about 150 mg per dose, depending on the diuretic selected.

[0113] For disease states which require prevention, reduction ortreatment of a cardiovascular disease state without incidence ofhyperkalemia, for example, the ALDO antagonist component, typicallyspironolactone, will be present in the therapy in an amount in a rangefrom about 1 mg to about 25 mg per dose. A preferred range forspirolactone would be from about 5 mg to 15 mg per dose. More preferablywould be a range from about 10 mg to 15 mg per dose per day.

[0114] The active ingredients may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier.

[0115] The dosage regimen for treating a disease condition with thecombination therapy of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex and medicalcondition of the patient, the severity of the disease, the route ofadministration, and the particular compound employed, and thus may varywidely.

[0116] For therapeutic purposes, the active components of thiscombination therapy invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the components may be admixed with lactose,sucrose, starch powder, cellulose esters of alkanoic acids, cellulosealkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide,sodium and calcium salts of phosphoric and sulfuric acids, gelatin,acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinylalcohol, and then tableted or encapsulated for convenientadministration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The components may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

[0117] Pharmaceutical compositions for use in the treatment methods ofthe invention may be administered in oral form or by intravenousadministration. Oral administration of the therapy is preferred. Dosingfor oral administration may be with a regimen calling for single dailydose, or for a single dose every other day, or for multiple, spaceddoses throughout the day. Where a combination therapy is desired, forexample, an aldosterone antagonist and a diuretic, the active agentswhich make up the combination therapy may be administeredsimultaneously, either in a combined dosage form or in separate dosageforms intended for substantially simultaneous oral administration. Theactive agents which make up the combinatin therapy may also beadministered sequentially, with either active component beingadministered by a regimen calling for two-step ingestion. Thus, aregimen may call for sequential administration of the active agents withspaced-apart ingestion of the separate, active agents. The time periodbetween the multiple ingestion steps may range from a few minutes toseveral hours, depending upon the properties of each active agent such apotency, solubility, bioavailability, plasma half-life and kineticprofile of the agent, as well as depending upon the age and condition ofthe patient. The active agents of the combined therapy whetheradministered simultaneously, substantially simultaneously, orsequentially, may involve a regimen calling for administration of oneactive agent by oral route and the other active agent by intravenousroute. Whether the active agents of the combined therapy are adminsteredby oral or intravenous route, separately or together, each such activeagent will be contained in a suitable pharmaceutical formulation ofpharmaceutically-acceptable excipients, diluents or other formulationscomponents. Examples of suitable pharmaceutically-acceptableformulations containing the active components for oral administrationare given below. Even though such formulations list both active agentstogether in the same recipe, it is appropriate for such recipe to beutilized for a formulation containing one of the active components.

EXAMPLE 1

[0118] An oral dosage may be prepared by screening and then mixingtogether the following list of ingredients in the amounts indicated. Thedosage may then be placed in a hard gelatin capsule. Ingredients Amountsspironolactone 12.5 mg magnesium stearate 10 mg lactose 100 mg

EXAMPLE 2

[0119] An oral dosage may be prepared by mixing together granulatingwith a 10% gelatin solution. The wet granules are screened, dried, mixedwith starch, talc and stearic acid, screened and compressed into atablet. Ingredients Amounts spironolactone 12.5 mg calcium sulfatedihydrate 100 mg sucrose 15 mg starch 8 mg talc 4 mg stearic acid 2 mg

EXAMPLE 3

[0120] An oral dosage may be prepared by screening and then mixingtogether the following list of ingredients in the amounts indicated. Thedosage may then be placed in a hard gelatin capsule. Ingredients Amountsspironolactone 12.5 mg furosemide 73.9 mg magnesium stearate 10 mglactose 100 mg

EXAMPLE 4

[0121] An oral dosage may be prepared by mixing together granulatingwith a 10% gelatin solution. The wet granules are screened, dried, mixedwith starch, talc and stearic acid, screened and compressed into atablet. Ingredients Amounts spironolactone 12.5 mg furosemide 73.9 mgcalcium sulfate dihydrate 100 mg sucrose 15 mg starch 8 mg talc 4 mgstearic acid 2 mg

[0122] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A pharmaceutical dosage comprising one or morepharmaceutically-acceptable excipients and spironolactone in an amountwhich is therapeutically effective to antagonize aldosterone but whichamount is not sufficient to induce substantial diuresis.
 2. The dosageof claim 1 wherein said subject is afflicted with or susceptible tocongestive heart failure and said subject further requires avoidance ofthe incidence of hyperkalemia.
 3. The dosage of claim 1 whereinspironolactone is present in a dose range from about 1 mg to about 23mg.
 4. The dosage of claim 3 wherein spironolactone is present in a doserange of about 5 mg to about 20 mg.
 5. The dosage of claim 4 whereinspironolactone is present in a dose of about 12.5 mg.
 6. A method totreat a circulatory disorder in a subject in need therof, said methodcomprising administering to said subject an amount of spironolactonesufficient to prevent or retard the development of congestive heartfailure but less than an amount to induce incidence of hyperkalemia. 7.The method of claim 6 comprising administering spironolactone in anamount that substantially avoids inducing diuresis.
 8. The method ofclaim 7 comprising administering spironolactone in an amount less than25 mg per day.
 9. The method of claim 8 comprising administeringspironolactone in an amount from about 5 mg to about 20 mg per day. 10.The method of claim 8 comprising administering spironolactone in anamount from about 5 mg to about 15 mg per day.
 11. The method of claim 8comprising administering spironolactone in an amount of about 12.5 mgper day.